The niche/microenvironment shapes the fate of researchers and stem cells

Transcription

1 The niche/microenvironment shapes the fate of researchers and stem cells Beate Heissig, MD Division of Stem Cell Dynamics Center of Stem Cell Biology and Regenerative Medicine The Institute of Medical Science The University of Tokyo

2 Current positions Visiting Associate Professor Juntendo University School of Medicine, Center for Atopy Principal Investigator Center for Stem Cell Biology and Regenerative Medicine Division of Stem Cell Dynamics The Institute of Medical Science

3 Career path High School, Germany Aachen & Marburg University (School of Medicine) 1990 M.D. Marburg University School of Medicine, Germany 1994 M.D. National Bone Marrow Donor Center, Tuebingen Physician, Tuebingen/Heidelberg University, Heidelberg University Medical School yrs Funding through German cancer society ; Post doc and Senior Research Associate at Weill Medical College of Cornell University, USA 2003 Funding through Humbolt Foundation/Germany (1yrs) and the Leukemia/lymphoma society; post-doc at Juntendo University 2004 Assistant Prof. at Institute of Medical Science, The University of Tokyo, Japan Funding through a mentor-based program: Frontier Research Initiative from MEXT) 2012 Associate Prof. at IMSUT, The University of Tokyo

4 Beate Heissig Publications before arrival in Japan Primary Reviews Salven P, et al. FASEB J. 16, , Rafii S, et al. Nat. Rev. Cancer 2, , Heissig B,* et al. Cell 109, , Rafii S, et al. Sem. Cell Dev. Biol. 13(1), 64-67, Heissig B,* et al. Nature Med. 8, , Wu Y, et al. Nature Medicine 7, , Rafii S, et al. Semin. Cell Dev. Biol. 13, 61-67, Rafii S, et al. Gene Therapy 9, , Sick C, et al. Ann. Hematol. 80, 9-16, Pasternak et al. Leukemia 13, Suppl. 1: S55-S64 (1999). Hattori K, et al. J. Exp. Med. 193, , Hattori K, et al. Blood 97, , Moore MA, et al. Ann. N. Y. Acad. Sci. 938, 36-45, Dias S*, et al. PNAS 98, , Lyden D, et al. Nat. Med Heissig B, et al. Leuk. Research 24, , Dias S, et al. J. Clin. Inv. 106, , Lane WJ, Dias S, et al. Blood 96, , Schultheis B, et al. Folia Biol. 46, , These publication and the research funds I brought lead to a Post doc and one year later to an Assistant Prof. position in Japan in Thanks to a mentor-based program from MEXT I became an Associate Professor in 2012.

5 Niche These days, we say that people have "found their niche" when they've found work they're good at and that they enjoy. Architecture: a recessed space (to keep a picture, sculpture protected) Ecology: function or position of a species within an ecological community. A specie s niche includes the physical environment to which it has become adapted and its role as producer and consumer of food resources

6 Stem cells and their niche In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some) can generate bone, cartilage, fat, cells that support the formation of blood, fibrous connective tissue, and extracellular matrix.

7 Niche cells ECM Mesenchymal stem cells Immune cells leukocytes Mesenchymal stem cells From: Mark et al., Nat Rev. Imm 2008

8 Matrix is everywhere : Extracellular matrix (ECM) In the body the extracellular matrix gives tissues their structural and mechanical properties The components of the matrix contribute to tissue specificity of cells NICHE CELLS require proteases to migrate through extracellular matrix to modify growth factor signaling, and to modify cellular adhesion

9 Stem cell expansion The proteolytic niche Proteases are enzymes that catalyze the breakdown of proteins by hydrolysis of peptide bonds. Cancer growth Tissue regeneration Activation Cyto-/chemokine (KitL, MCP-1, CXCL5) Change of receptor specificity Inactivation Cell receptors, ligands (e.g. upar) BM matrix proteins (e.g. laminin) Inflammation Degradation Adhesion molecules (e.g. VCAM-1) Extracellular matrix Mod from: Heissig ADDR, 2015

10 Lab focus Hematopoiesis = blood cell generation Proteases in the niche/microenvironment Angiogenesis = blood vessel generation Physiological: daily blood cell production, and tissue development. Pathological: blood cell regeneration after chemotherapy, in diseases like blood cell cancer (leukemia), and inflammation. Physiological: during wound healing, and tissue development. Pathological: during tissue regeneration, in diseases like atherosclerosis, hind limb ischemia, rheumatoid arthritis, diabetic retinopathy and cancer.

11 tpa-m SC cont-m SC Current studies using various disease models to studying protease functions 1 Blood vessels for tissue regeneration and Stem cell maintenance Hematopoietic stem cell expansion Niche cell expansion Dahri et al Blood Pro-MMP9 Plasminogen Plasmin tpa Before dif. Adipo Osteo Chondro Ohki et al. Blood 2012 Tashiro et al. Blood Cancer Ishihara et al., Leukemia 2012 Oil Red O Alkaline phosphatase Toluidine bl Protease +/+ and -/- mice 3 Inflammation Blood cell transplantation rejection (GvHD), inflammatory bowel disease Surgery induced colon adhesion TNF-a Sato, Leukemia 2015 Munakata, Gastroenterology 2015 Protease/PAI1 inhibitor Honjo, FASEB, in Revision

12 THE LAB NICHE MATRIX Language Funding PI if the lab Niche inhabitants Jap./foreign students Technician Office personal Researcher within the institute or outside

13 Problems for foreigners to establish a functional niche - When you leave your country of origin you leave the protective niche, where you know the support system (senior scientists/zenpai, knowledge on funding etc.). - Arriving in a foreign country, you join a lab with the general expectation that you will return to your home country. So the PI usually does not feel mentorship responsibility (career development). - If you made it and established a laboratory it is hard to recruit native (e.g. Japanese) students and technical stuff, because Japanese fear that they are not able to reenter the Japanese network system (researcher niche) to promote them after they leave the lab. - Grant applications in Japan require more and more networking and support collaboration-based science, which foreigners often do not have. As a foreigner you often attract foreign student, you grow up foreign researchers who return to their own countries. They will not feed back in your local support (zenpai) system that in the future helps you: e.g. as local collaborators. A niche can protect, but also isolate.

14 Suggestion: Individual development plan (IDP) based on mentorship PROBLEM: No mentorship for foreigner researcher. Foreign researcher are regarded as migratory rather than permanent worker. MENTORSHIP for Foreign researcher (post doc, senior scientist) Foreign researcher Foreign researcher Foreign researcher Foreign researcher

15 Beate Heissig FUTURE PLAN JOB OFFER: a technician with native Japanese skills (latest from 4/2017) a post doc position in case your salary is fully funded SEEKING: collaborations with foreign researchers in various research fields to do joint research and establish a network heissig@ims.u-tokyo.ac.jp